Rene M. Koenigs

Unifying metal and Brønsted acid catalysis--concepts, mechanisms, and classifications.

Asymmetric catalysis is a key feature of modern synthetic organic chemistry. Traditionally, different combinations of ligands and metals are used to perform highly enantioselective reactions. Since the renaissance of organocatalysis in the early 2000s, tremendous improvement in the field of metal-free catalysis has been achieved. Recently, the combination of transition metals and organocatalysts has allowed the development of new protocols enabling transformations that could not previously be realized. This article aims to present the latest contributions in the field of combined chiral Brønsted acid and metal catalyzed reactions, highlighting the advantages of these catalytic systems as well as describing the uncertainties regarding the molecular structure of the catalytically active species and the reaction mechanisms.

Dual Catalysis: Combination of Photocatalytic Aerobic Oxidation and Metal Catalyzed Alkynylation Reactions—CC Bond Formation Using Visible Light

A new dual catalytic system for efficient C[BOND]H functionalization was developed. The appropriate choice of two metal catalysts allows the oxidative alkynylation of tertiary amines under mild and sustainable reaction conditions.

Light‐Mediated Heterogeneous Cross Dehydrogenative Coupling Reactions: Metal Oxides as Efficient, Recyclable, Photoredox Catalysts in CC Bond‐Forming Reactions

Let there be light: A heterogeneous photocatalytic system based on easily recyclable TiO(2) or ZnO allows cross dehydrogenative coupling reactions of tertiary amines. The newly developed protocols have successfully been applied to various C-C and C-P bond-forming reactions to provide nitro amines as well as amino ketones, nitriles and phosphonates.

Fluoroalkyl-Substituted Diazomethanes and Their Application in a General Synthesis of Pyrazoles and Pyrazolines

A novel continuous-flow approach for the synthesis of fluoroalkyl-substituted diazomethanes has been developed. Utilizing a cheap, self-made microreactor fluoroalkyl-substituted amines were transformed into the corresponding diazomethanes using tert-butyl nitrite and acetic acid as catalyst. These diazomethanes were employed in [2+3] cycloaddition reactions with olefins and alkynes, yielding valuable pyrazolines and pyrazoles in good to excellent yields.

Efficient Enantioselective Synthesis of Optically Active Diols by Asymmetric Hydrogenation with Modular Chiral Metal Catalysts

The enantioselective hydrogenation of prochiral ketones is one of the most elegant and effective methods for the preparation of optically active secondary alcohols. With regard to the environment, asymmetric hydrogenations represent a highly efficient and atom-economical process. Multiple applications have been developed using chiral ruthenium complexes with atropisomeric ligands for the synthesis of optically active primary and secondary alcohols. The latter are important building blocks for the synthesis of natural products, pharmaceuticals and, agrochemicals. The development of a general and efficient enantioselective route to terminal, vicinal 1,2-diols still presents a great challenge. These compounds are important chiral building blocks for the synthesis of natural products such as macrodiolides, insect pheromones, b-lactone esterase inhibitors, d-lactones, and many other biologically active substances. 5] In the synthesis of the anti-HIV pharmaceutical Tenofovir and related pharmaceuticals the application of enantiomerically pure (R)-propane-1,2-diol is of critical importance. A further application of terminal optically active 1,2-diols is the resolution of atropisomeric compounds. The asymmetric dihydroxylation of terminal alkenes is the most common method for the preparation for this class of compounds. However, small sterically less demanding alkyl derivatives, such as propene, cannot be enantioselectively oxidized to the diol by asymmetric dihydroxylation, nor to the epoxide by asymmetric epoxidation. The difficulty in the highly enantioselective transformation of small alkyl derivatives arises from the similar steric demands of the two groups adjacent to the carbonyl functionality. The result is poor Re and Si face differentiation for the sterically less demanding alkyl derivatives; in contrast, the sterically more demanding aryl ketones can be readily differentiated (Figure 1). The hydrogenation of a-hydroxy ketones is one alternative for the generation of valuable optically active, terminal 1,2-diols. Good progress has been made in the hydrogenation of the sterically demanding a-hydroxy acetophenones using various ruthenium and iridium catalysts. Rhodium and ruthenium complexes were also successfully applied in asymmetric transfer hydrogenations. Further work concentrated on asymmetric enzymatic reductions. A general, reductive, and highly enantioselective synthesis of aliphatic 1,2-diols has not been reported previously. Therefore, we began our examination of the enantioselective synthesis of optically active diols with the application of a new class of modular diphosphane ligands 1. Particular attention was given to nonsymmetric ligands as these were considered more suitable for the enantioface differentiation of the alkyl hydroxy ketones, which are more challenging substrates. Ligands 1 can be prepared simply in two steps on a large scale and are based on a 2,5-disubstituted thiophene core structure, a chiral phospholane unit, 13] and a readily variable diarylphosphino group (Scheme 1).

Fluorinated diazoalkanes – a versatile class of reagents for the synthesis of fluorinated compounds

Although diazoalkanes find regular application in organic synthesis, the synthesis and application of their fluorinated homologues was long neglected. First described in 1943, trifluorodiazoethane found its way into the organic synthesis repertoire only in the past decade for atom-economical and practical synthesis of fluorinated building blocks and currently emerges as a versatile reagent. The synthetic applicability of this reagent is currently being investigated in great detail and many interesting new reactivities, and procedures for the synthesis of fluoroalkyl-substituted building blocks have been developed. In this context, a range of new fluoroalkyl substituted diazoalkanes have been introduced in the past few years, ranging from perfluorinated diazoalkanes towards highly reactive difluorodiazoethane which was first described in 2015. This tutorial review covers historic milestones of fluoroalkyl substituted diazoalkanes and highlights recent examples which underscore their vast potential to the synthesis of fluorinated compounds.

Rhodium catalyzed synthesis of difluoromethyl cyclopropanes

Difluoromethyl-substituted cyclopropanes still remain one of the most challenging class of substrates. Despite significant progress in modern chemistry, an atom-economic and concise synthesis has not been described to date. Herein, we describe the first method for their catalytic, one-step synthesis using difluoromethyl diazomethane and a rhodium(ii) catalyst.

Difluoro- and trifluoro diazoalkanes – complementary approaches in batch and flow and their application in cycloaddition reactions

Herein we report on applications of fluorinated diazoalkanes in cycloaddition reactions, with the emphasis on studying subtle differences between diverse fluorinated diazo compounds. These differences led to two major synthetic protocols in batch and flow that allow the safe and scalable synthesis of fluoroalkyl-, sulfone-substituted pyrazolines.

Corey–Chaykovsky Reactions of Nitro Styrenes Enable cis-Configured Trifluoromethyl Cyclopropanes

Trifluoromethyl-substituted cyclopropanes are an attractive family of building blocks for the construction of pharmaceutical and agrochemical agents. This work demonstrated the utilization of fluorinated sulfur ylides as versatile reagents for Corey-Chaykovsky cyclopropanation reactions of nitro styrenes. This protocol favored the synthesis of cis-configured trifluoromethyl cyclopropanes for a broad range of substrates with excellent yields and good diastereoselectivities.

Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

Diazo acetonitrile has long been neglected despite its high value in organic synthesis due to a high risk of explosions. Herein, we report our efforts towards the transient and safe generation of this diazo compound, its applications in iron catalyzed cyclopropanation and cyclopropenation reactions and the gram-scale synthesis of cyclopropyl nitriles.